LEONARDA-1: Phase III randomized study of lerociclib plus fulvestrant in patients with HR+, HER2- locally advanced or metastatic breast cancer that has progressed on prior endocrine therapy.
Authors: Binghe Xu, Qingyuan Zhang, Yang Luo, Zhongsheng Tong, Tao Sun, Changping Shan, Xinlan Liu, Yumin Yao, Bing Zhao, Shusen Wang, Xiaohua Zeng, Changlu Hu, Xi Yan, Xiaojia Wang, Hongyan Jia, Zhendong Chen, Fuming Qiu, Xinhong Wu, Deyong Zhang, Tong Li
Journal: Journal of Clinical Oncology (2023)

1017 Background: Lerociclib (GB491), a novel oral CDK4/6 inhibitor with continuously daily dosing, which has demonstrated anti-tumor response and a differentiated safety &amp; tolerability profile in previous clinical trials. The LEONARDA-1 study assessed the efficacy of lerociclib and fulvestrant in endocrine-resistant advanced BC. Methods: This is a randomized, double-blind, placebo-controlled phase III study assessing lerociclib in combination with fulvestrant in pre/peri-menopausal or postmenopausal, HR+, HER2- locally advanced or metastatic BC patients (pts) who had relapsed or progressed on prior endocrine therapy (ET). Eligible patients were allowed one prior line of chemotherapy for metastatic disease. Pre-/peri-menopausal pts also received goserelin. Pts were randomized 1:1 to receive lerociclib (150mg po bid, d1-28, q4w) or placebo (P) plus fulvestrant (F). The primary endpoint was investigator-assessed progression-free survival (PFS) based on RECIST v1.1. Secondary endpoints included PFS (assessed by BICR), overall survival (OS), response assessment, safety and tolerability, pharmacokinetic (PK) profile. Results: By December 2 nd 2022 as data cut-off date, 275 pts were randomized, 137 to receive lerociclib + F and 138 to P + F. Median follow-up time was 7.36 months (range, 0.03-11.93+) for lerociclib + F vs 7.33 months (range, 0.03-11.27) for P + F. Baseline characteristics were well balanced (The median age was 54 years and 53.5 years, 41.6%% and 44.9% were Pre/peri-menopausal, 64.2% and 62.3% had visceral disease, 24.8% and 26.1% were primary resistant to prior ET, 28.5% and 29.0% received one line of chemotherapy for metastatic disease, respectively). At the time of cut-off date, 125 PFS events were observed with a median PFS of 11.07 months for lerociclib + F and 5.49 months for P + F (HR: 0.458; 95% CI: 0.317, 0.661, P&lt; 0.001 by log-rank test). In patients with measurable disease (n=240, 87.3%), the ORR was significantly higher in lerociclib + F 26.9% (2.5% complete response [CR]) vs 9.9% (0% CR) for P + F. Consistent benefit from lerociclib was seen in pre/peri-menopausal and postmenopausal subjects. The most common adverse events (AEs) for lerociclib + F versus P + F were neutropenia (90.5% vs. 4.3%), leucopenia (86.9% vs. 6.5%), anemia (34.3% vs. 10.1%), thrombocytopenia (19.7% vs. 3.6%), and diarrhea (19.7% vs. 3.6%). Grade 3 or 4 neutropenia was reported in 46.7% pts on lerociclib + F (G3: 41.6%, G4: 5.1%) vs 0% pts on P + F. There was no case of ≥Grade3 diarrhea reported. The discontinuation rate due to AEs was 0.7% on lerociclib + F and 0% on P + F. Serious AEs were reported for 5.8% and 8.0%, respectively. Conclusions: Lerociclib at 150mg twice daily plus fulvestrant significantly improved PFS and ORR and demonstrated a favorable tolerable safety profile in pts with HR+ / HER2- endocrine-resistant advanced BC. Clinical trial information: NCT05054751 .